Poor Sleep quality and health-related quality of life impact in adolescents with and without chronic immunosuppressive conditions during COVID-19 quarantine

OBJECTIVE: To assess the possible factors that influence sleep quality in adolescents with and without chronic immunosuppressive conditions quarantined during the coronavirus disease 2019 (COVID-19) pandemic. METHODS: This cross-sectional study included 305 adolescents with chronic immunocompromised conditions and 82 healthy adolescents. Online surveys were completed, which included questions on socio-demographic data and self-rated healthcare routine during COVID-19 quarantine and the following validated questionnaires: the Pittsburgh Sleep Quality Index (PSQI), Pediatric Quality of Life Inventory 4.0 (PedsQL4.0), and Pediatric Outcome Data Collection Instrument (PODCI). RESULTS: The median current age [14 (10-18) vs. 15 (10-18) years, p=0.847] and frequency of female sex (62% vs. 58%, p=0.571) were similar in adolescents with chronic conditions compared with healthy adolescents. The frequency of poor sleep quality was similar in both groups (38% vs. 48%, p=0.118). Logistic regression analysis, including both healthy adolescents and adolescents with chronic conditions (n=387), demonstrated that self-reported increase in screen time (odds ratio [OR] 3.0; 95% confidence interval [CI] 1.3-6.8; p=0.008) and intrafamilial violence report (OR 2.1; 95% CI 1.2-3.5; p=0.008) were independently associated with poor sleep quality in these adolescents. However, the PODCI global function score was associated with a lower OR for poor sleep quality (OR 0.97; 95% CI 0.94-0.99; p=0.001). Further logistic regression, including only adolescents with chronic conditions (n=305), demonstrated that self-reported increase in screen time (OR 3.1; 95% CI 1.4-6.8; p=0.006) and intrafamilial violence report (OR 2.0; 95% CI 1.2-3.4; p=0.011) remained independently associated with poor quality of sleep, whereas a lower PODCI global function score was associated with a lower OR for sleep quality (OR 0.96; 95% CI 0.94-0.98; p<0.001). CONCLUSION: Self-reported increases in screen time and intrafamilial violence report impacted sleep quality in both healthy adolescents and those with chronic conditions. Decreased health-related quality of life was observed in adolescents with poor sleep quality.


' INTRODUCTION
The new coronavirus disease  emerged in China at the end of 2019 and precipitated a global health crisis (1,2). Moreover, the policies adopted by governments to reduce the spread of this disease, such as social distancing, face mask use, stay-at-home orders, and closure of schools and leisure activities, resulted in abrupt changes in daily routines and lifestyles (2,3).
These changes might affect sleep patterns and physical and mental health and wellbeing (4). Indeed, during this pandemic, adolescents are experiencing more flexible awakening time, reduced exposure to sunlight, prolonged day naps, increased exposure to ''blue light,'' and disruption of melatonin production (5). Recent studies have reported that an increase in screen time (6), mental health disorders (5), and intrafamilial violence (7) may contribute to poor sleep quality in pediatric and adult populations during the COVID-19 pandemic.
Adolescents with chronic immunosuppressive conditions have complex diseases, requiring coordination of multiple specialties, humanized care, and different treatment approaches (8). The impact on physical health, sleep quality, and health-related quality of life (HRQL) parameters may affect these adolescents during this emergent crisis (9). However, to the best of our knowledge, the concomitant analysis of validated tools of sleep quality and HRQL was not systematically assessed in this vulnerable group quarantined during the COVID-19 pandemic.
Therefore, this study aimed to assess sleep quality parameters in adolescents with chronic immunosuppressive conditions and healthy adolescents during the COVID-19 quarantine period. We also evaluated the possible association of poor-quality sleep with demographic data, information about COVID-19 and HRQL parameters in adolescents with chronic immunosuppressive conditions.

' MATERIALS AND METHODS
From July to October 2020, a cross-sectional study using an online survey was performed with 704 adolescents aged 10-18 years during the COVID-19 pandemic in Brazil. Of these, 555 adolescents had chronic immunocompromised conditions and were followed at our tertiary and referral hospital (10,11); 250 adolescents were excluded because they did not answer the online survey (n=152) or because of incomplete survey data (n=98). Thus, 305 adolescents with chronic immunocompromised conditions comprised the study group.
After approval of parents/legal guardians, 149 healthy adolescents were recruited by advertisement on radio, television, daily newspapers, Facebook, and Instagram. Of these healthy adolescents, 67 were excluded because of refusal to participate in the present study (n=23) and because of incomplete survey data (n=44). Therefore, 82 healthy adolescents were included in the control group. None of them reported a previous diagnosis of mental health disorders before the COVID-19 pandemic or other acute or chronic conditions.
The first contact with all participants was made by phone calls for a brief conversation. Psychological and psychiatric support was offered to adolescents with chronic immunosuppressed diseases and healthy adolescents, particularly those who reported any signs or symptoms of mental health issues.
To create and to distribute the survey, we used the Research Electronic Data Capture (REDCap s ) application. The online survey was answered using cellphones, computers, or tablets. At least six emails or WhatsApp messages were forwarded to increase the response frequency. This study was approved by the Brazilian National Committee for Research Ethics (CONEP number: 4.081.961). All parents/ legal guardians and adolescents provided informed consent and assent at the beginning of the online survey.
The online survey comprised four parts, predominantly based on information from the previous month. The estimated time for responses was approximately 45 min. The first part of the survey contained questions about sociodemographic data, school, healthcare routine, general information about COVID-19, impact of quarantine, and physical health during the COVID-19 pandemic (Appendix) for which the response formats were multiple choice, dichotomous (yes and no), or ordinal based on the visual analogue scale (VAS) (ranging from 0-10). Previous diagnoses of mental disorders before the COVID-19 pandemic were also systematically recorded.
The second part of the survey was composed of the Pittsburgh Sleep Quality Index (PSQI) (21), which comprises 19 questions regarding sleep quality and disorders. This instrument evaluates seven sleep categories: sleep latency, sleep duration, sleep efficiency, sleep disturbance, sleep medication use, overall sleep quality, and daytime dysfunction because of sleepiness. Each score varied from 0 to 3 for each element, and the PSQI total score ranged from 0 to 21. A total score 45 points was defined as poor sleep quality and p5 points as good sleep quality (18).
The third part of the survey was a self-report generic version of the Pediatric Quality of Life Inventory 4.0 (PedsQL) (22), which measured HRQL in four multidimensional scales: physical, emotional, social, and school functioning. The survey contains 23 items that are scored on a five-point scale. The sum of the two summary scores (physical health summary score and psychosocial health summary score) generates the total PedsQL score. The answers are given on a five-point scale ranging from 0 (''almost always'') to 100 (''never''), with higher scores indicating better HRQL.
The fourth part of the survey was a self-report version of the Pediatric Outcome Data Collection Instrument (PODCI) (23), a generic questionnaire with 83 questions developed to evaluate HRQL. It is divided into five subscales (upper extremity and physical functioning, transfer and basic mobility, sports and physical functioning, pain/comfort, and happiness) and a PODCI global function score, each ranging from 0 to 100. Lower scores indicated a lower HRQL.

Statistical analyses
The sample size of 387 adolescents provided a power of 80% to find differences greater than 31% of poor sleep quality among adolescents with chronic immunocompromised conditions and healthy controls (GraphPad StatMate 1.01, GraphPad Software, Inc., CA, USA). Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) for Windows 24.0 (IBM Corp., Armonk, NY, USA). The results were described as numbers and frequencies for categorical variables and as median, minimum, and maximum values or means ± standard deviations for continuous variables. The scores that had a non-normal distribution were compared using the Mann-Whitney test. Differences in categorical variables were evaluated using Fisher's exact test or Pearson's chi-square test, as indicated. Spearman rank correlation coefficient was used for analyzing the correlation between the total PSQI score and PedsQL, PODCI, and VAS (physical activity [PA] scale, disease activity/complication, fear of immunosuppressive use, and fear of COVID-19). Logistic regression analysis models (forward stepwise) were performed using poor sleep quality as a dependent variable and variables that presented a statistical significance level of po0.2 in the univariate analyses as independent variables, in adolescents with chronic immunosuppressive conditions and healthy controls. Statistical significance was set at po0.05.
Demographic data and the PSQI, PedsQL, and PODCI scores reported by adolescents with chronic immunosuppressive conditions versus those reported by healthy adolescents during the COVID-19 quarantine are shown in Table 1. The frequencies of poor sleep quality were similar in both groups (38% vs. 48%, p=0.118), whereas the means of sleep latency (1.11 ± 1.02 vs. 1.37 ± 1.05, p=0.043) and day dysfunction because of sleepiness (0.71±0.78 vs. 1.01±0.87, p=0.003) according to PSQI score were significantly lower in adolescents with chronic immunosuppressive conditions than in healthy controls. Adolescents with chronic conditions had a higher median happiness scale by the PODCI than healthy controls [85 (5-100) vs. 75 (0-100), p=0.025]. Additional evaluations of poor sleep quality, the PSQI total score, the PedsQL total scale score and its subscales, and the PODCI global function score and its subscales were similar in both groups (all p40.05, Table 1).
Further comparisons between adolescents with chronic immunosuppressive conditions and poor sleep quality (total PSQI score 45) compared with those with good sleep quality (total PSQI score p5) during the COVID-19 quarantine showed that the frequency of adolescents in public school was significantly higher in the former group (79% vs. 68%, p=0.036). Moreover, adolescents with chronic  However, the PODCI global function score was associated with a lower odds of poor sleep quality (OR, 0.97; 95% CI, 0.95-0.99; p=0.004).
Adolescents who presented with signs or symptoms of mental health issues were systematically assessed by pediatric psychologists. Eighteen adolescents with chronic conditions and healthy controls had private online appointments with psychologists, including eight of whom reported intrafamilial violence in the online survey. None of the eight adolescents with chronic conditions reported any kind of violence during appointments with pediatric psychologists.
Spearman correlations between the PSQI total score and independent variables are shown in Table 4. The final models of logistic regression analyses to evaluate independent factors associated with poor sleep quality are included in Table 5.

' DISCUSSION
Our study was the first to evaluate adolescents with chronic immunosuppressive conditions during the COVID-19 pandemic and the temporal relationship between various dimensions of sleep quality using PSQI and HRQL instruments.
One strength of this study was the use of self-report validated instruments with high reliability to measure sleep quality and HRQL. In addition, the current report evaluated a vulnerable and high-risk subgroup of adolescents who had more severe restrictions during the COVID-19 quarantine because of their chronic immunosuppressed conditions. Furthermore, the inclusion of a healthy control group adjusted for age and sex allowed a more precise analysis of the influence of chronic immunosuppressive conditions on sleep quality, as demographic features may impact sleep problems differently (5,6).
According to the PSQI results, approximately 40% of adolescents with chronic immunocompromised conditions and healthy adolescents had poor sleep quality during the COVID-19 pandemic. Healthy adolescents demonstrated higher sleep latency and daytime sleepiness than chronic immunosuppressed patients.
The COVID-19 pandemic caused by the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to numerous health problems and decreased HRQL parameters among the general public worldwide (5,6,24,25). Our study demonstrated that the COVID-19 pandemic equally impacted HRQL in adolescents with chronic conditions and healthy adolescents. However, adolescents with chronic immunosuppressive conditions reported higher happiness scores by the PODCI than their healthy peers. Adolescents with chronic illnesses may have more coping mechanisms, since they learn how to deal with suffering and pain from a   We confirmed previous studies regarding the influence of screen time on sleep quality in healthy adolescents and those with chronic immunosuppressive conditions. Zhou et al. found that healthy adolescents and young adults who had increased mobile phone use, playing online games, and online shopping suffered from decreased sleep hygiene and quality and prolonged sleep latency (5). Additionally, a study from Chile reported that an increase in screen time was associated with a decline in sleep quality in children (6). Moreover, Nagata et al. showed that an increase in screen time may decrease physical activity in adolescents with obesity (28).
Of note, to the best of our knowledge, our study is the first to find an association between poor sleep quality and selfreported increase in screen time in adolescents with various chronic immunosuppressed conditions. This result may be related to the fact that more time expended in front of screens could lead adolescents to have less time to sleep (29). In addition, adolescents with chronic conditions and poor sleep quality attended predominantly public schools, and the absence of school activities during this cross-sectional study may have contributed to insomnia and sleep issues in this population.
During the COVID-19 pandemic period, studies have shown that increased sedentary behavior can influence sleep patterns in pediatric populations. Our study found an inverted association between the PSQI total score and increased physical activity per week using the VAS. Similarly, López-Bueno et al. demonstrated that a decrease in health-related behaviors leads to a reduction in weekly minutes of physical activity (30). Moreover, a study conducted in Verona revealed that physical activity was reduced by 2.5h per week during quarantine (31). Physical activity is crucial to healthy living and noticeably decreases the risk of systemic inflammation (32). Consequently, physical activity has a potential role in immune functions that are helpful in reducing the risk of infectious diseases from the perspective of the COVID-19 outbreak. Therefore, it is important to implement policies that encourage the practice of indoor exercise.
The COVID-19 pandemic has collateral effects ranging beyond those of viral infections. Importantly, intrafamilial violence reported by healthy adolescents and those with chronic immunosuppressive conditions impacted their quality of sleep. In fact, violence against adolescents is a serious public health, human rights, and social issue, with numerous traumatic consequences. However, it has rarely been reported in adolescents with multiple complex conditions. A recent systematic review studied the most important negative effects of school closings and social distancing during the COVID-19 pandemic, and suspected domestic violence was observed with an increase in domestic accidents and head trauma (33). Further qualitative studies, including ethical considerations for adolescents with private structured interviews, will be performed for this vulnerable population to clarify these findings and to assess the spectrum of violence, including physical/emotional aggression, negligence, and sexual abuse. If it is necessary for their own protection, adolescents experiencing violence will be promptly referred to the responsible legal sectors, such as the Protective Council and Child and Youth Court.
This study has some limitations. Our data came from only one tertiary center, which could have led to a selection bias. The cross-sectional design limited our ability to ascertain the causal relationship between the COVID-19 pandemic and changes in HRQL and sleep quality. During the COVID-19 pandemic, adolescents were overloaded with online activity, which could have affected the ratio of responses to the questionnaires. We only have data from one period of the COVID-19 pandemic, making it impossible to objectively compare with previous baseline situations. We did not assess generic or specific mental health tools, especially validated instruments concerning anxiety, depression, and coping/ resilience. The online survey is another limitation of this study, because of the self-report nature of the questionnaires, at only a single instance. There is a risk of recall bias. We also analyzed only one question regarding self-reported increase in screen time during the pandemic and did not assess the total period of screen time, as well as television time, smartphone use, and computer use.
In conclusion, self-reported increases in screen time and intrafamilial violence report impacted sleep quality in both healthy adolescents and those with chronic conditions. Decreased HRQL was observed in adolescents with poor sleep quality.